Novolog Mix 70-30

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NovoLog Mix 70/30

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Administration

The short and long-acting components of insulin mixes, including NovoLog Mix
70/30, cannot be titrated independently. Because NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) has peak
pharmacodynamic activity between 1-4 hours after injection, it should be administered
within 15 minutes of meal initiation [see CLINICAL PHARMACOLOGY]. The
dose of insulin required to provide adequate glycemic control for one of the
meals may result in hyper- or hypoglycemia for the other meal. The pharmacodynamic
profile may also be inadequate for patients who require more frequent meals.

NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) should not be mixed with any other insulin product.

NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) should not be used intravenously.

NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) should not be used in insulin infusion pumps.

Glucose monitoring is recommended for all patients with diabetes. Any change
of insulin dose should be made cautiously and only under medical supervision.
Changing from one insulin product to another or changing the insulin strength
may result in the need for a change in dosage. Changes may also be necessary
during illness, emotional stress, and other physiologic stress in addition to
changes in meals and exercise.

The pharmacokinetic and pharmacodynamic profiles of all insulins may be altered
by the site used for injection and the degree of vascularization of the site.
Smoking, temperature, and exercise contribute to variations in blood flow and
insulin absorption. These and other factors contribute to inter- and intra-patient
variability.

NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) FlexPen is for use by one person only.

Hypoglycemia

Hypoglycemia is the most common adverse effect of insulin therapy, including
NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) . Severe hypoglycemia may lead to unconsciousness and/or convulsions
and may result in temporary or permanent impairment of brain function or even
death. Severe hypoglycemia requiring the assistance of another person and/or
parenteral glucose infusion or glucagon administration has been observed in clinical trials with insulin, including trials with NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) .

The timing of hypoglycemia may reflect the time-action profile of the insulin
formulation [see CLINICAL PHARMACOLOGY]. Other factors, such as changes
in dietary intake (e.g., amount of food or timing of meals), injection site,
exercise, and concomitant medications may also alter the risk of hypoglycemia
[See DRUG INTERACTIONS]. As with all insulins, use caution in patients
with hypoglycemia unawareness and in patients who may be predisposed to hypoglycemia
(e.g. patients who are fasting or have erratic food intake). The patient's ability
to concentrate and react may be impaired as a result of hypoglycemia. This may
present a risk in situations where these abilities are especially important,
such as driving or operating machinery.

Rapid changes in serum glucose levels may induce symptoms of hypoglycemia in
persons with diabetes, regardless of the glucose value. Early warning symptoms
of hypoglycemia may be different or less pronounced under certain conditions,
such as long duration of diabetes, diabetic nerve disease, use of medications
such as beta-blockers, or intensified diabetes control [see DRUG INTERACTIONS].

Hypokalemia

All insulin products, including NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) , cause a shift in potassium
from the extracellular to intracellular space, possibly leading to hypokalemia
that, if left untreated, may cause respiratory paralysis, ventricular arrhythmia,
and death. Use caution in patients who may be at risk for hypokalemia (e.g.
patients using potassium-lowering medications or patients taking medications
sensitive to potassium concentrations).

Renal Impairment

Clinical or pharmacology studies with NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) in diabetic patients
with various degrees of renal impairment have not been conducted. As with other
insulins, the requirements for NovoLog Mix 70/30 may be reduced in patients
with renal impairment. [see CLINICAL PHARMACOLOGY]

Hepatic Impairment

Clinical or pharmacology studies with NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) in diabetic patients
with various degrees of hepatic impairment have not been conducted. As with
other insulins, the requirements for NovoLog Mix 70/30 may be reduced in patients
with hepatic impairment. [see CLINICAL PHARMACOLOGY]

Hypersensitivity and Allergic Reactions

Local Reactions- As with other insulin therapy, patients may experience
reactions such as erythema, edema or pruritus at the site of NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin))
injection. These reactions usually resolve in a few days to a few weeks, but
in some occasions, may require discontinuation of NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) . In some
instances, these reactions may be related to the insulin molecule, other components
in the insulin preparation including protamine and cresol, components in skin
cleansing agents, or injection techniques. Localized reactions and generalized
myalgias have been reported with the use of cresol as an injectable excipient.

Systemic Reactions- Less common, but potentially more serious, is generalized
allergy to insulin, which may cause rash (including pruritus) over the whole
body, shortness of breath, wheezing, reduction in blood pressure, rapid pulse,
or sweating. Severe cases of generalized allergy, including anaphylactic reaction,
may be life threatening.

Antibody Production

Specific anti-insulin antibodies as well as cross-reacting anti-insulin antibodies
were monitored in a 3-month, open-label comparator trial as well as in a long-term
extension trial. Changes in cross-reactive antibodies were more common after
NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) than with Novolin® 70/30 but these changes did not correlate
with change in HbA1c or increase in insulin dose. The clinical significance
of these antibodies has not been established. Antibodies did not increase further
after long-term exposure ( > 6 months) to NovoLog Mix 70/30.

Patient Counseling Information

Physician Instructions

Maintenance of normal or near-normal glucose control is a treatment goal in
diabetes mellitus and has been associated with a reduction in diabetic complications.
Patients should be informed about potential risks and advantages of NovoLog
Mix 70/30 therapy including the possible adverse reactions. Patients should
also be offered continued education and advice on insulin therapies, injection
technique, life-style management, regular glucose monitoring, periodic glycosylated hemoglobin testing, recognition and management of hypo- and hyperglycemia, adherence
to meal planning, complications of insulin therapy, timing of dose, instruction
for use of injection devices, and proper storage of insulin. See PATIENT INFORMATION supplied with the product. Patients should be informed that frequent, patient-performed
blood glucose measurements are needed to achieve optimal glycemic control and
avoid both hyper- and hypoglycemia, and diabetic ketoacidosis.

The patient's ability to concentrate and react may be impaired as a result
of hypoglycemia. This may present a risk in situations where these abilities
are especially important, such as driving or operating other machinery. Patients
who have frequent hypoglycemia or reduced or absent warning signs of hypoglycemia
should be advised to use caution when driving or operating machinery.

Accidental substitutions between NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) and other insulin products
have been reported. Patients should be instructed to always carefully check
that they are administering the appropriate insulin to avoid medication errors
between NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) and any other insulin. The prescription for NovoLog
Mix 70/30 should be written clearly in order to avoid confusion with other insulin
products, for example, NovoLog or Novolin 70/30. In addition, the written
prescription should clearly indicate the presentation, for example FlexPen or
vial.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Standard 2-year carcinogenicity studies in animals have not been performed
to evaluate the carcinogenic potential of NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) . In 52-week studies,
Sprague-Dawley rats were dosed subcutaneously with NovoLog, the rapid-acting
component of NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) , at 10, 50, and 200 U/kg/day (approximately 2,
8, and 32 times the human subcutaneous dose of 1.0 U/kg/day, based on U/body
surface area, respectively). At a dose of 200 U/kg/day, NovoLog increased the incidence of mammary gland tumors in females when compared to untreated controls.
The incidence of mammary tumors found with NovoLog was not significantly different
from that found with regular human insulin. The relevance of these findings
to humans is not known.

In fertility studies in male and female rats, NovoLog at subcutaneous doses
up to 200 U/kg/day (approximately 32 times the human subcutaneous dose, based
on U/body surface area) had no direct adverse effects on male and female fertility,
or on general reproductive performance of animals.

Use In Specific Populations

Pregnancy

Pregnancy Category B

All pregnancies have a background risk of birth defects, loss, or other adverse
outcome regardless of drug exposure. This background risk is increased in
pregnancies complicated by hyperglycemia and may be decreased with good metabolic
control. It is essential for patients with diabetes or history of gestational
diabetes to maintain good metabolic control before conception and throughout
pregnancy. Insulin requirements may decrease during the first trimester, generally
increase during the second and third trimesters, and rapidly decline after
delivery. Careful monitoring of glucose control is essential in such patients.

An open-label, randomized study compared the safety and efficacy of NovoLog
(the rapid-acting component of NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) ) versus human insulin in the
treatment of pregnant women with Type 1 diabetes (322 exposed pregnancies (NovoLog:
157, human insulin: 165)). Two-thirds of the enrolled patients were already
pregnant when they entered the study. Since only one-third of the patients
enrolled before conception, the study was not large enough to evaluate the risk
of congenital malformations. Mean HbA1c of ~ 6% was observed in both groups
during pregnancy, and there was no significant difference in the incidence of
maternal hypoglycemia.

Animal reproduction studies have not been conducted with NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) .
However, subcutaneous reproduction and teratology studies have been performed
with NovoLog (the rapid-acting component of NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) ) and regular
human insulin in rats and rabbits. In these studies, NovoLog was given to female
rats before mating, during mating, and throughout pregnancy, and to rabbits
during organogenesis. The effects of NovoLog did not differ from those observed
with subcutaneous regular human insulin. NovoLog, like human insulin, caused
pre- and post-implantation losses and visceral/skeletal abnormalities in rats
at a dose of 200 U/kg/day (approximately 32-times the human subcutaneous dose
of 1.0 U/kg/day, based on U/body surface area), and in rabbits at a dose of
10 U/kg/day (approximately three times the human subcutaneous dose of 1.0 U/kg/day,
based on U/body surface area). The effects are probably secondary to maternal
hypoglycemia at high doses. No significant effects were observed in rats at
a dose of 50 U/kg/day and rabbits at a dose of 3 U/kg/day. These doses are approximately
8 times the human subcutaneous dose of 1.0 U/kg/day for rats and equal to the
human subcutaneous dose of 1.0 U/kg/day for rabbits based on U/body surface
area.

Female patients should be advised to discuss with their physician if they intend
to, or if they become pregnant. There are no adequate and well-controlled studies
of the use of NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) in pregnant women.

Nursing Mothers

It is unknown whether insulin aspart is excreted in human milk as occurs with
human insulin. There are no adequate and well-controlled studies of the use
of NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) or NovoLog in lactating women. Women with diabetes who
are lactating may require adjustments of their insulin doses.

Pediatric Use

Safety and effectiveness of NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) have not been established in
pediatric patients.

Geriatric Use

Clinical studies of NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) did not include sufficient numbers of
patients aged 65 and over to determine whether they respond differently than
younger patients. In general, dose selection for an elderly patient should
be cautious, usually starting at the low end of the dosing range reflecting
the greater frequency of decreased hepatic, renal, or cardiac function, and
of concomitant disease or other drug therapy in this population.

Last reviewed on RxList: 6/9/2010
This monograph has been modified to include the generic and brand name in many instances.